CD40L modulates CD4 + T cell activation through receptor for activated C kinase 1.

Inhibition of the co-stimulatory ligand CD40L has shown beneficial effects in many experimental models of auto-immune disease and inflammation. Here, we show that CD40L deficiency in T-cells in mice causes a reduction of CD4 + T cell activation and specifically a strong reduction in interferon- γ (IFN-γ) producing T helper 1 (Th1) cells. In vitro, we could not reproduce this APC-dependent effects, but found that T-cell CD40L affects cell death and proliferation. We identified receptor of activated C kinase (RACK1), the canonical PKC binding partner and known to drive proliferation and apoptosis, as a mediator of CD40L reverse signaling. Furthermore, we found that CD40L clustering stabilizes IFN-γ mediated Th1 polarization through STAT1, a known binding partner of RACK1. Together this highlights the importance of both CD40L forward and reverse signaling. This article is protected by copyright. All rights reserved.